Certain 1H-indole-3-glyoxamides are known to be potent and selective inhibitors of mammalian sPLA.sub.2 useful for treating diseases, such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis and related sPLA.sub.2 induced diseases. EPO publication No. 0675110, for example, discloses such compounds.
Various patents and publications describe processes for making indole-3-glyoxamides.
The article, "Recherches en serie indolique. VI sur tryptamines substituees", by Marc Julia, Jean Igolen and Hanne Igolen, Bull. Soc. Chim. France, 1962, pp. 1060-1068, describes certain indole-3-glyoxylamides and their conversion to tryptamine derivatives.
The article, "2-Aryl-3-Indoleglyoxylamides (FGIN-1): A New Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR)" by E. Romeo, et al., The Journal of Pharmacology and Experimental Therapeutics, Vol. 262, No. 3, (pp. 971-978) describes certain 2-aryl-3-indolglyoxylamides having research applications in mammalian central nervous systems.
The abstract, "Fragmentation of N-benzylindoles in Mass Spectrometry"; Chemical Abstracts, Vol. 67, 1967, 73028h, reports various benzyl substituted phenols including those having glyoxylamide groups at the 3 position of the indole nucleus.
U.S. Pat. No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus.
U.S. Pat. No. 3,351,630 describes alpha-substituted 3-indolyl acetic acid compounds and their preparation inclusive of glyoxylamide intermediates.
U.S. Pat. No. 2,825,734 describes the preparation of 3-(2-amino-1-hydroxyethyl)indoles using 3-indoleglyoxylamide intermediates such as 1-phenethyl-2-ethyl-6-carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30).
U.S. Pat. No. 4,397,850 prepares isoxazolyl indolamines using glyoxylamide indoles as intermediates. U.S. Pat. No. 3,801,594 describes analgesics prepared using 3-indoleglyoxylamide intermediates.
The article, "No. 565.--Inhibiteurs d'enzymes. XII.--Preparation de (propargylamino-2 ethyl)-3 indoles" by A. Alemanhy, E. Fernandez Alvarez, O. Nieto Lopey and M. E. Rubio Herraez; Bulletin De La Societe Chimique De France, 1974, No. 12, pp. 2883-2888, describes various indolyl-3 glyoxamides which are hydrogen substituted on the 6-membered ring of the indole nucleus.
The article "Indol-Umlagerung von 1-Diphenylamino-2,3-dihydro-2,3-pyrrolidonen" by Gert Kollenz and Christa Labes; Liebigs Ann. Chem., 1975, pp. 1979-1983, describes phenyl substituted 3-glyoxylamides.
Allowed U.S. application Ser. No. 08/469954, now U.S. Pat. No. 5,654,326, herein incorporated by reference in its entirety, discloses a process for preparing 4-substituted-1H-indole-3-glyoxamide derivatives comprising reacting an appropriately substituted 4-methoxyindole (prepared as described by Clark, R. D. et al., Synthesis, 1991, pp 871-878, the disclosures of which are herein incorporated by reference) with sodium hydride in dimethylformamide at room temperature (20-25.degree. C.) then treating with arylmethyl halide at ambient temperatures to give the 1-arylmethylindole which is O-demethylated using boron tribromide in methylene chloride (Tsung-Ying Shem and Charles A. Winter, Adv. Drug Res., 1977, 12, 176, the disclosure of which is incorporated by reference) to give the 4-hydroxyindole. Alkylation is achieved with an alpha bromoalkanoic acid ester in dimethylformamide using sodium hydride as a base. Conversion to the glyoxamide is achieved by reacting the .varies.-[(indol-4-yl)oxy]alkanoic acid ester first with oxalyl chloride, then with ammonia, followed by hydrolysis with sodium hydroxide in methanol.
The process for preparing 4-substituted-1H-indole-3-glyoxamide derivatives, as set forth above, has utility. However, this process uses expensive reagents and environmentally hazardous organic solvents, produces furan containing by-products and results in a relatively low yield of desired product.
The present invention provides an improved process for preparing 4-substituted-1H-indole-3-glyoxamide derivatives. The process of the present invention can be performed with inexpensive, readily available, reagents using aqueous solvent systems and resulting in better overall yield while avoiding the production of furan byproducts. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims.